Bryan Chow and Simon W. Rabkin. 1. Introduction

Cardiology Research and Practice Volume 2013, Article ID 986847, 7 pages http://dx.doi.org/10.1155/2013/986847 Clinical Study Brachial-Ankle Pulse Wave Velocity Is the Only Index of Arterial Stiffness That Correlates with a Mitral Valve Indices of Diastolic Dysfunction, but No Index Correlates with Left Atrial Size Bryan Chow and Simon W. Rabkin Department of Medicine (Cardiology), University of British Columbia, Level 9, 2775 Laurel Street, Vancouver, BC, Canada V5Z 1M9 Correspondence should be addressed to Simon W. Rabkin; rabkin@mail.ubc.ca Received 3 December 2012; Accepted 11 February 2013 AcademicEditor:F.H.H.Leenen Copyright 2013 B. Chow and S. W. Rabkin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The objective of this study was to determine the optimal assessment of arterial stiffness that relates to diastolic dysfunction. Forty-one patients had measurements of brachial-ankle pulse wave velocity (bapwv), carotid-femoral pulse wave velocity (cfpwv), ankle brachial index (ABI), pulse pressure (PP), and augmentation index (AIx). Diastolic dysfunction was evaluated by echocardiographic indices of the ratio of the peak early diastolic mitral valve velocity and the peak late diastolic velocity (E/A ratio), left atrial diameter, and left atrial volume indexes. There was a significant (P < 0.05) correlation between bapwv and E/A ratio with an inverse relationship indicating that higher arterial stiffness was associated with greater diastolic dysfunction. In contrast, there was no significant correlation between E/A ratio and cfpwv, PP, ABI, or AIx. After multivariate analysis, the relationship between bapwv and E/A ratio remained significant (P < 0.05), independent of age and systolic blood pressure (BP). There were no correlations between any index of vascular stiffness and left atrial dimension or volume. In summary, bapwv correlates with diastolic dysfunction, independent of a patient s age and BP and is a better indicator of diastolic dysfunction than other indicators of arterial stiffness. bapwv has the utility of infering the presence of left ventricular diastolic dysfunction. 1. Introduction Compromised left ventricular diastolic function represents an ongoing cardiovascular challenge from the perspective of its detection, assessment, and management [1, 2]. The early detection of diastolic dysfunction has garnered increasing attention because it predicts the development of heart failure [3, 4]. Currently, the primary imaging modality for assessing left ventricular diastolic function is Doppler echocardiography although there are controversies in the precision of its assessment [5 8]. It can require the integration of transmitral flow, pulmonary venous flow, mitral annular motion, myocardial deformation, and cardiac structure. This complex measurement of diastolic function can be reduced to several common elements the assessment of transmitral flow velocity and evaluation of cardiac structure which includes left atrial size [1, 8]. The ratios of peak early diastolic mitral flow filling velocity (E) and of the peak late mitral diastolic filling velocity (A), E/A ratio, characterize the severity and stage of the diastolic dysfunction [9]. In diastolic dysfunction, the E/A ratio decreases as E velocity is reduced and A velocity is increased [9]. Because ageing alters the E/A ratio, age adjustment is necessary [6]. Another component of the assessment of diastolic dysfunction is left atrial (LA) dimension. LA size or volume has been proposed as a simple noninvasive assessment of the degree of LV diastolic dysfunction [10]. LA size is increased, and LA emptying is decreased in patients with diastolic heart failure [11]. While the role of arterial stiffness in prediction of cardiovascular events is well documented[12 15], the capacity of arterial stiffness to alter left ventricular diastolic function is less certain. Arterial stiffness is hypothesized to produce LV diastolic dysfunction through increased cardiac after load [16, 17] and reduced coronary perfusion; the latter is hypothesized to produce LV diastolic dysfunction through decreased diastolic blood pressure [18]. The concept that

2 Cardiology Research and Practice systolic arterial loading can impair subsequent diastolic function, however, was not substantiated by investigators using the more direct assessment of myocardial relaxation by examining LV pressure decay during early diastole or tau [19]. In addition, the proposition that arterial stiffness impairs left ventricular relaxation and subsequent diastolic dysfunction has had mixed clinical evidence, with some studies supporting the presence of an association [20], some are equivocal [21], while other studies found no relationship [22]. Some of the studies that reported a relationship between arterial stiffness and diastolic dysfunction did not adjust for factors such as age [20] that affect arterial stiffness and diastolic dysfunction independently. Variations in reports may in part be due to differences in techniques for the measurement of arterial stiffness. Pulse wave velocity (PWV) is a validated method to quantify arterial stiffness [23] and can be measured in different arterial segments, with brachial-ankle PWV (bapwv) and carotidfemoral PWV (cfpwv) being the most common ones. Augmentation index (AIx), pulse pressure (PP), and increased ankle brachial index (ABI) are also indices of arterial stiffness. AIx has traditionally been considered to represent increased wave reflection [24], while more recently increased AIx has been attributed to a reduction in the reservoir function compliance properties of the aorta and other elastic arteries [25]. Increased arterial stiffness produces an increase in systolic blood pressure and reduction in diastolic blood pressure which is easily recognized by an increase in pulse pressure [26]. Increased ABI, occurring in the absence of peripheral arterial disease, indicates a greater augmentation in systolic arterial pressure as the pulse wave moves the longer distance to the ankle arteries compared to the shorter distance to the brachial arteries, and it is due to an increase in arterial stiffness [27]. Which of these indices of arterial stiffness, if any, best identifies a relationship with diastolic dysfunction needs to be determined? The objective of this study was to determine whether arterial stiffness is related to left ventricular diastolic dysfunction and to determine which of four indices of arterial stiffness bapwv, cfpwv, ABI, or pulse pressure correlated best with an echocardiographic assessment of diastolic dysfunction. 2. Methods Patients from a cardiology clinic at a University teaching hospital who met the following criteria were studied. Men or women over the age of 45 years that agreed to participate in the study were included. Patients were only included if they had a satisfactory echocardiographic assessment without significant aortic or mitral valve diseases or impairment in left systolic ventricular function identified on echocardiographic assessment. A noninvasive measure of vascular stiffness was performed as previously outlined [27, 28]. PWV and augmentation index were measured on an Omron Colin VP1000/2000 (Ill, USA). Briefly, the subject was examined while resting in the supine position, with electrocardiogram electrodes placed on both wrists and a microphone for detecting heart sounds placed on the left edge of the sternum. Blood pressure cuffs, which were connected to the device, were placed around both arms and ankles. After the participants rested in the supine position, the right carotid pulse wave and femoral artery contours were recorded simultaneously by placement of a transducer over these arteries. Using the carotid pressure waveform, the augmentation index (AIx) was calculated as the difference between the second and the first systolic shoulder and was expressed as a percentage of the carotid pulse contour. PWV was calculated as the ratio of the distance in meters from the brachial artery to ankle or carotid to femoral artery and the transit time in seconds, measured from the basal level of one pulse to the other either bapwv or cfpwv. Cardiac structure and function were assessed according to a standardized protocol. Two-dimensional echocardiograms were performed. Parasternal long- and short-axes views were used to determine left ventricular end-diastolic and end-systolic measurements and wall thickness dimensions and left atrial diameter according to the recommendations of the American Society of Echocardiography [29]. Diastolic function was determined using Doppler assessment of mitral inflow velocity specifically peak early and late diastolic mitral flow velocities. Left atrial volume was measured using the biplane area-length method determined from the apical 4 chamber view. Left atrial volume was indexed by body surface area. All measurements were recorded by an ultrasonographer unaware of the clinical condition of the participants. All numeric data are expressed as mean values (±SD), and categorical data are present at percentages. Univariate and multivariate regression analyses were conducted using PASW Statistics 18. Statistical significance was set at P < 0.05. 3. Results The study population consisted of 41 adult patients (mean age 68 ± 11 years, 66% male) of whom 73% had hypertension and 12% had diabetes mellitus (Table 1). The echocardiographic data indicate that the group had a normal systolic function with an ejection fraction of 63.3 ± 5%. There was a significant correlation between bapwv and E/A ratio (Figure 1). The relationship was negative, indicating a decreasing E/A ratio with increases in bapwv. None of the other indices of arterial stiffness, cfpwv, ABI, or Aix, correlated significantly withe/a ratio (Table 2). Measuresofleftatrialsize, leftatrial diameter (LAD) and left atrial volume index (LAVI), did not correlate significantly with any index of arterial stiffness. LADcorrelatedsignificantlywithage.Thenumberofsubjects without hypertension is small and precluded meaningful separate analysis. Because bapwv and cfpwv comprise some of the same elements of arterial stiffness, the relationship between bapwv and cfpwv was explored by a linear correlation analysis. There was a significant relationship between the two factors with an r value of 0.717 or r 2 value of 0.514 (Figure 2). The line of identity demonstrates that bapwv exceeds

Cardiology Research and Practice 3 Table 1: Clinical characteristics of the study population. Number of subjects 41 Age (years) 68 ± 11 Gender (% men) 66 BMI (kg/m 2 ) 26.7 ± 3.6 BSA (m 2 ) 1.84± 0.22 Hypertension (%) 73.2 Dyslipidemia (%) 48.8 Diabetes (%) 12.2 CAD (%) 22.0 Medications β-blockers (%) 34.1 ACEIs (%) 36.6 ARBs (%) 7.3 CCBs (%) 24.4 Statins (%) 43.9 Aspirin (%) 53.7 Antiplatelets (%) 14.6 Diuretics (%) 19.5 Heart rate (bpm) 67.3 ± 12.8 SBP (mm Hg) 138.5 ± 18.1 DBP (mm Hg) 78.8 ± 8.4 PP (mm Hg) 59.7 ± 14.2 bapwv (cm/s) 1814 ± 415 cfpwv (cm/s) 1610 ± 500 AIx (%) 20.0 ± 18.3 ABI 1.14 ± 0.12 LAD (mm) 36.8 ± 6.5 LAVI (ml/m 2 ) 33.5± 11.7 E (cm/s) 79.6 ± 26.0 A (cm/s) 76.0 ± 25.5 E/A 1.15 ± 0.54 Age < 60: 1.3 ± 0.4 Age 60: 1.1 ± 0.6 LVEF (%) 63.3 ± 5.0 LVM (g) 151.2 ± 36.6 LVMI (g/m 2 ) 80.3 ± 21.0 LVDD (mm) 45.0 ± 5.1 LVSD (mm) 28.4 ± 5.5 IVST (mm) 10.0 ± 1.4 PWT (mm) 9.7 ± 1.2 BMI: body mass index, BSA: body surface index, CAD: coronary artery disease, ACEIs: angiotensin-converting enzyme inhibitors, ARBs: angiotensin II receptor antagonists, CCBs: calcium channel blockers, SBP: systolic blood pressure, DBP: diastolic blood pressure, PP: pulse pressure, ABI: anklebrachial index, Aix: augmentation index, cfpwv: carotid-femoral pulse wave velocity, bapwv: brachial-ankle pulse wave velocity, LAD: left atrial diameter, LAVI: left atrial volume index, E:peakearlydiastolicfillingvelocity, A: peak late diastolic filling velocity, E/A: E/A ratio; LVEF: left ventricular ejection fraction, LVM: left ventricular mass, LVMI: left ventricular mass index, LVDD: left ventricular end-diastolic diameter, LVSD: left ventricular end-systolic diameter, IVS: interventricular septal end-diastolic thickness, and PWT: posterior wall end-diastolic thickness. cfpwv on a consistent basis. bapwv was 17% greater than cfpwv. Age was positively correlated with bapwv (P < 0.001) and cfpwv (P < 0.001). There were also significant positive Table 2: Univariate correlates between echocardiographic variables and indices of arterial stiffness. E/A LAd LAVI r P r P r P bapwv 0.311 0.04 0101 0.52 0.008 0.96 cfpwv 0.040 0.11 0.119 0.45 0.213 0.18 PP 0.152 0.34 0.260 0.10 0.238 0.13 ABI 0.156 0.32 0.096 0.55 0.135 0.40 AIx 0.044 0.78 0.048 0.76 0.098 0.54 Age 0.180 0.26 0.313 0.04 0.210 0.18 SBP 0.170 0.28 0.144 0.36 0.108 0.50 r: pearson correlation coefficient; other abbreviations as in Table 1. Indicates P < 0.05. correlations between systolic blood pressure (SBP) and both bapwv (P = 0.044) and cfpwv (P = 0.002). Pulse pressure was significantly correlated with cfpwv (P = 0.007), but IT did not correlate significantly with bapwv or AIx. There was a significant positive correlation between age and pulse pressure (P = 0.015). The relationship between age and indices of aortic stiffness necessitates the use of multivariate analysis in order to consider the potential effect of age on the relationship between aortic stiffness and E/A ratio. A significant association between bapwv and E/A ratio persisted after adjusting forage,sbp,andppinamultipleregressionanalysis(table 3). Multivariate analysis was utilized, in case one of the variables was obscuring a relationship between cfpwv and E/A ratio. AgeandSBPweresignificantlycorrelatedwithcfPWVin multivariate analysis. There was no significant relationship between cfpwv and E/A ratio after multiple regression analysis (Table 4). 4. Discussion The major contribution of this study is the comparative analysis of different indices of arterial stiffness and their association with left ventricular diastolic dysfunction. We found that bapwv was significantly correlated with an indicator of diastolic dysfunction, and the association was independent of age and blood pressure. Importantly, bapwv was a better predictor of diastolic dysfunction than several other indices of arterial stiffness, namely, cfpwv, AIx, PP, or ABI. Both bapwv and cfpwv are indicators of arterial stiffness, and each of them is related to cardiovascular morbidity and mortality [14, 15, 30 32]. With regards to diastolic dysfunction, recent investigations have mainly examined either bapwv [22, 33 37] or cfpwv[20, 38 41] in relation to E/A ratio. We compared bapwv and cfpwv and found a significant relationship between diastolic dysfunction and bapwv but not with cfpwv. It was not our purpose to compare bapwv versus cfpwv over the spectrum of cardiovascular diseases; we rather focused solely on the association with an index of left ventricular diastolic function and found a greater utility for bapwv. While both bapwv and cfpwv are indicators of arterial stiffness, bapwv is an indicator of the combination of central and peripheral

4 Cardiology Research and Practice Table 3: Multivariate analysis for bapwv. Model Unstandardized Standardized 95% Confidence Sig beta S.E. Beta t for beta E/A 455.5 215.065.588 2.118.042 892.604 18.473 Age 26.9 4.959.751 5.418.000 16.791 36.947 SBP 21.5 6.315.937 3.401.002 8.644 34.310 PP 23.7 8.286.811 2.854.007 40.489 6.810 cfpwv (cm/s) E/A ratio 4 3 2 1 0 r = 0.311 P < 0.05 0 1000 2000 3000 bapwv (cm/s) Figure 1: The relationship between bapwv and E/A ratio. 3000 2000 1000 0 r = 0.717 P < 0.05 0 1000 bapwv (cm/s) 2000 Figure 2: The relationship between bapwv and cfpwv. 3000 arterial stiffness [31, 42 44]. Our study suggests that the effects of peripheral arterial stiffness on ventricular diastolic function are better represented by the greater arterial path measured by bapwv as compared to the centrally confined path of cfpwv. While bapwv and cfpwv are highly and significantly correlated with each other, the correlation is far from being identical. We found a r 2 of 0.513, indicating that only about 50% of the variance of oneisaccountedforbytheother.thisvalueissimilarto the one reported by others (r 2 = 0.63) [42]. We found that bapwv was predominantly greater than cfpwv by 17%. Thisisconsistentwithanotherreportthatshowsthat,on average, bapwv was approximately 20% higher than cfpwv [42]. The higher value presumably reflects the additional contribution of peripheral (or muscular) arterial stiffness to central arterial stiffness [43]. bapwv recognizes a different vascular stiffness pathway, and, is one differently affected by interventions such as weight loss [45]. The association of bapwvwithanincreasedriskoftotalcardiovascularevents and all-cause mortality [15] may reflect the effect of bapwv on the heart. OurfindingthatbaPWVcorrelateswithLVdiastolic function is consistent with several studies [34, 35, 37] but they did not compare bapwv with a wide range of other measurements of arterial stiffness. Wang et al. compared PWV measurements in the brachial-ankle, carotid-femoral, heart-femoral, and heart-carotid segments among hypertensive patients and also found bapwv to be the best predictor of diastolic dysfunction amongst measurements of PWV [46]. However, they did not conduct a multivariate analysis adjusting for age and blood pressure [46] two factors that influence diastolic cardiac function. Age and systolic blood pressure are the two primary determinants of bapwv and cfpwv as we found and as has been reported previously [42]. Therefore, our measurements of PWV were adjusted for these two parameters. With advancing age, arterial stiffness increases due to changes in arterial elasticity and compliance, leading to elevations in systolic pressures and pulse pressure [47 49]. Prolonged elevations in blood pressure can also independently lead to similar changes in the vasculature that increases arterial stiffness [50, 51]. The associations of age, SBP, and PP with bapwv and cfpwv are confirmed in the present study. After including these factors in multivariate analysis, the negative relationship between bapwv and E/A ratio remained significant,andthebapwvrelationshipwithmitralvalve velocity measurements was independent of age, SBP, and PP. We did not find any associations between indices of arterial stiffness and left atrial size assessment either by left atrial diameter or left atrial volume. While left atrial size has been purported to be a marker of chronic diastolic dysfunction and cardiovascular disease risk [52], previous data on the relationship of left atrial size and arterial stiffness have been limited and somewhat conflicting. One study reported no significant association between PWV or pulse pressure and left atrial size but an association between AIx and left atrial size [21]. Another study reported a significant correlation between cfpwv and left atrial diameter [39]. Brachial-ankle

Cardiology Research and Practice 5 Table 4: Multivariate analysis for cfpwv. Model Unstandardized Standardized 95% Confidence Sig Beta S.E. Beta t for beta E/A 21.990 278.229.024.079.937 587.418 543.438 Age 26.356 6.415.611 4.108.000 13.319 39.393 SBP 22.997 8.170.833 2.815.008 6.395 39.600 PP 18.876 10.720.537 1.761.087 40.661 2.909 SBP is systolic blood pressure. PP is pulse pressure. PWV and cfpwv correlated with left atrial diameter in patients with hypertension, end-stage renal disease, and heart failure [53]. One potential explanation for the differences between studies is the differences in the proportion of other factors that influence left atrial size in each of the study population. Left atrial size is larger in patients with hypertension and in the elderly as well as patients with reduced left ventricular systolic function [11, 22]. The proportion of individualswitheachofthesecharacteristicslikelyinfluenced the relationship between left atrial size and arterial stiffness. Our study consisted of individuals with normal LV systolic function. Augmentation index was not associated with diastolic dysfunction in our study. This finding is consistent with two studies [21, 54] but contrasts with the findings of two another studies [55, 56]. While AIx is an indicator of arterial stiffness, pulse wave velocity more closely correlates with adverse cardiovascular outcomes [57]. We did not find any relationship between pulse pressure and diastolic function. Ourfindingsareconsistentwithsomepreviousdatathatsay that PWV is superior to central and brachial pulse pressures for the detection of diastolic dysfunction in older adults with preserved LV ejection fraction [58]. Several possible limitations of this study should be considered. The patient population is relatively small. However, significant correlations were still found. Secondly, the changes in E/A ratio with the progression of diastolic dysfunctionaresuchthattheinitialimpairmentofdiastolicfunction is manifested as a decreased E/A ratio. In long standing disease, changes in ventricular and atrial structure occur, and the diastolic dysfunction may predominantly have a restrictive pattern, which is manifested as an increased E/A ratio [6]. Others however disagree with this postulated pattern of progression [8]. The use of decreasing E/A ratio as an indicator of diastolic dysfunction is appropriate in this study that consists of a study population without severe cardiac disease. Third, we focused mainly on E/A ratio as an indicator of diastolic dysfunction. Mitral valve velocities and myocardial tissue Doppler measurements can provide additional important data on the state of diastolic function. However, each of these measurements has unique limitations in their correlation with more precise measurements of diastolic function [8]. Importantly, E/A ratioremainsastandardamongthefield of the detection of diastolic dysfunction. Fourth, subjects were on antihypertensive drugs that can impact on arterial stiffness and minimize the wave reflection thereby altering the relative strength of the relationship between different indices of arterial stiffness and diastolic function [59]. Fifth, we use the term arterial stiffness recognizing that this term may encompass abnormalities in separate measures of arterial compliance, distensibility, pressure augmentation, or wave reflection in different segments of the vasculature. In summary, the present study shows that increased bapwv is associated with diastolic dysfunction, measured by E/A ratio. Age, SBP, and PP were major determinants of increased bapwv, but the relationship between bapwv and E/A ratio was independent of these clinical variables. Our findings show that bapwv is more closely correlated with E/A ratio than with other indices of arterial stiffness, namely cfpwv, AIx, ABI, or pulse pressure. The more extensive arterial pathway measured by bapwv in comparison to cfpwv may explain this relationship. These data suggest that measuring bapwv has the utility of infering or suspecting thepresenceofleftventriculardiastolicdysfunction. Conflict of Interests The authors declare that they have no conflict of interests. References [1] B. A. Borlaug and W. J. Paulus, Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment, European Heart Journal, vol. 32, no. 6, pp. 670 679, 2011. [2] J. J. McMurray, S. Adamopoulos, S. D. Anker et al., ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure2008.thetaskforceforthediagnosisandtreatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM), European Heart Failure, vol. 10, no. 10, pp. 933 989, 2008. [3] G. C. Kane, B. L. Karon, D. W. Mahoney et al., Progression of left ventricular diastolic dysfunction and risk of heart failure, JournaloftheAmericanMedicalAssociation,vol.306,no.6,pp. 856 863, 2011. [4]C.S.P.Lam,A.Lyass,E.Kraigher-Kraineretal., Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community, Circulation,vol.124,no.1,pp.24 30,2011. [5] C. Tschöpe and W. J. Paulus, Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular

6 Cardiology Research and Practice diastolic pressures, Circulation, vol. 120, no. 9, pp. 810 819, 2009. [6]S.F.Nagueh,C.P.Appleton,T.C.Gillebertetal., Recommendations for the evaluation of left ventricular diastolic function by echocardiography, the American Society of Echocardiography,vol.22,no.2,pp.107 133,2009. [7] W. C. Little and J. K. Oh, Echocardiographic evaluation of diastolic function can be used to guide clinical care, Circulation,vol. 120, no. 9, pp. 802 809, 2009. [8] K. O. Ogunyankin, Assessment of left ventricular diastolic function: the power, possibilities, and pitfalls of echocardiographic imaging techniques, Canadian Cardiology, vol.27,no.3,pp.311 318,2011. [9] R. A. Nishimura and A. J. Tajik, Evaluation of diastolic filling of left ventricle in health and disease: doppler echocardiography is the clinician s Rosetta Stone, the American College of Cardiology,vol.30,no.1,pp.8 18,1997. [10] C. L. Simek, M. D. Feldman, H. L. Haber, C. C. Wu, A. R. Jayaweera, and S. Kaul, Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function, the American Society of Echocardiography,vol.8,no.1,pp.37 47,1995. [11] J. S. Gottdiener, D. W. Kitzman, G. P. Aurigemma, A. M. Arnold, andt.a.manolio, Leftatrialvolume,geometry,andfunction in systolic and diastolic heart failure of persons 65 years of age (The Cardiovascular Health Study), The American Cardiology,vol.97,no.1,pp.83 89,2006. [12] C. Vlachopoulos, K. Aznaouridis, M. F. O Rourke, M. E. Safar, K. Baou, and C. Stefanadis, Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis, European Heart Journal,vol.31, no.15,pp.1865 1871,2010. [13] F. U. S. Mattace-Raso, T. J. M. Van Der Cammen, A. Hofman et al., Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study, Circulation, vol. 113, no. 5, pp. 657 663, 2006. [14] S. Laurent, P. Boutouyrie, R. Asmar et al., Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients, Hypertension, vol. 37, no. 5, pp. 1236 1241, 2001. [15] C. Vlachopoulos, K. Aznaouridis, D. Terentes-Printzios, N. Ioakeimidis, and C. Stefanadis, Prediction of cardiovascular events and all-cause mortality with brachial-ankle elasticity index: a systematic review and meta-analysis, Hypertension, vol. 60, no. 2, pp. 556 562, 2012. [16] T.Weber,M.F.O Rourke,M.Ammer,E.Kvas,C.Punzengruber, and B. Eber, Arterial stiffness and arterial wave reflections are associated with systolic and diastolic function in patients with normal ejection fraction, AmericanJournalofHypertension, vol.21,no.11,pp.1194 1202,2008. [17] B. A. Borlaug, V. Melenovsky, M. M. Redfield et al., Impact of arterial load and loading sequence on left ventricular tissue velocities in humans, the American College of Cardiology, vol. 50, no. 16, pp. 1570 1577, 2007. [18] I. Guelen, F. U. S. Mattace-Raso, N. M. Van Popele et al., Aortic stiffness and the balance between cardiac oxygen supply and demand: the Rotterdam Study, Hypertension,vol.26, no. 6, pp. 1237 1243, 2008. [19] M.R.Starling,D.G.Montgomery,G.B.J.Mancini,andR.A. Walsh, Load independence of the rate of isovolumic relaxation in man, Circulation,vol.76, no.6,pp. 1274 1281, 1987. [20] G. Soldatos, K. Jandeleit-Dahm, H. Thomson et al., Large artery biomechanics and diastolic dysfunctionin patients with Type 2 diabetes, Diabetic Medicine, vol.28,no.1,pp.54 60, 2011. [21] W. P. Abhayaratna, M. E. Barnes, M. F. O Rourke et al., Relation of arterial stiffness to left ventricular diastolic function and cardiovascular risk prediction in patients 65 years of age, The American Cardiology, vol. 98, no. 10, pp. 1387 1392, 2006. [22] P. C. Hsu, T. H. Lin, C. S. Lee et al., Mismatch between arterial stiffness increase and left ventricular diastolic dysfunction, Heart and Vessels, vol. 25, no. 6, pp. 485 492, 2010. [23] R. Asmar, A. Benetos, J. Topouchian et al., Assessment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies, Hypertension, vol.26,no.3,pp.485 490,1995. [24] M. F. O Rourke and W. W. Nichols, Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension, Hypertension, vol. 45, no. 4, pp. 652 658, 2005. [25] J. E. Davies, J. Baksi, D. P. Francis et al., The arterial reservoir pressure increases with aging and is the major determinant of theaorticaugmentationindex, American Physiology, vol. 298, no. 2, pp. H580 H586, 2010. [26] W. W. Nichols, M. F. O Rouke, and C. Vlackopoulos, McDonald s Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles, Hodder Arnold, London, UK, 2011. [27] S. W. Rabkin, S. H. Chan, and C. Sweeney, Ankle-brachial index as an indicator of arterial stiffness in patients without peripheral artery disease, Angiology, vol. 63, pp. 150 154, 2012. [28] S. W. Rabkin and S. H. Chan, Correlation of pulse wave velocity with left ventricular mass in patients with hypertension once blood pressure has been normalized, Heart International, vol. 7, p. e5, 2012. [29] R. M. Lang, M. Bierig, R. B. Devereux et al., Recommendations for chamber quantification: a report from the American Society of Echocardiography s guidelines and standards committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology, the American Society of Echocardiography,vol.18,no.12,pp.1440 1463, 2005. [30] T. C. Turin, Y. Kita, N. Rumana et al., Brachial-ankle pulse wave velocity predicts all-cause mortality in the general population: findings from the Takashima study, Japan, Hypertension Research, vol. 33, no. 9, pp. 922 925, 2010. [31] A. Yamashina, H. Tomiyama, K. Takeda et al., Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement, Hypertension Research,vol.25,no.3,pp.359 364,2002. [32]M.Nakamura,T.Yamashita,J.Yajimaetal., Brachial-ankle pulse wave velocity as a risk stratification index for the shortterm prognosis of type 2 diabetic patients with coronary artery disease, Hypertension Research, vol. 33, no. 10, pp. 1018 1024, 2010. [33] Y.Usui,Y.Takata,Y.Inoueetal., Severeobstructivesleepapnea impairs left ventricular diastolic function in non-obese men, Sleep Medicine,vol.4,p.4,2011. [34] L.Xu,C.Q.Jiang,T.H.Lametal., Arterialstiffnessandleftventricular diastolic dysfunction: Guangzhou Biobank Cohort Study-CVD, Human Hypertension,vol.25, no.3,pp. 152 158, 2011. [35] C. M. Chung, C. M. Chu, S. T. Chang et al., Quantification of aortic stiffness to predict the degree of left ventricular diastolic

Cardiology Research and Practice 7 function, American the Medical Sciences,vol.340,no. 6, pp. 468 473, 2010. [36] M. Yambe, H. Tomiyama, Y. Hirayama et al., Arterial stiffening as a possible risk factor for both atherosclerosis and diastolic heart failure, Hypertension Research,vol.27,no.9,pp.625 631, 2004. [37] H. Masugata, S. Senda, K. Yoshikawa et al., Relationships between echocardiographic findings, pulse wave velocity, and carotid atherosclerosis in type 2 diabetic patients, Hypertension Research,vol.28,no.12,pp.965 971,2005. [38] G. Soldatos, K. Jandeleit-Dahm, H. Thomson et al., Large artery biomechanics and diastolic dysfunctionin patients with type 2 diabetes, Diabetic Medicine,vol.28,no.1,pp.54 60,2011. [39] H. Triantafyllidi, S. Tzortzis, J. Lekakis et al., Association of target organ damage with three arterial stiffness indexes according to blood pressure dipping status in untreated hypertensive patients, American Hypertension, vol. 23, no. 12, pp. 1265 1272, 2010. [40] C. Tsioufis, D. Chatzis, K. Dimitriadis et al., Left ventricular diastolic dysfunction is accompanied by increased aortic stiffness in the early stages of essential hypertension: a TDI approach, Hypertension,vol.23,no.9,pp.1745 1750, 2005. [41] C. D. Libhaber, G. R. Norton, O. H. I. Majane et al., Contribution of central and general adiposity to abnormal left ventricular diastolic function in a community sample with a high prevalence of obesity, The American Cardiology,vol. 104, no. 11, pp. 1527 1533, 2009. [42] H. Tanaka, M. Munakata, Y. Kawano et al., Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness, JournalofHypertension, vol. 27, no. 10, pp. 2022 2027, 2009. [43]J.Sugawara,K.Hayashi,T.Yokoietal., Brachial-anklepulse wave velocity: an index of central arterial stiffness? Human Hypertension,vol.19,no.5,pp.401 406,2005. [44] M.Munakata,N.Ito,T.Nunokawa,andK.Yoshinaga, Utility of automated brachial ankle pulse wave velocity measurements in hypertensive patients, American Hypertension,vol. 16, no. 8, pp. 653 657, 2003. [45] J. N. Cooper, J. M. Buchanich, A. Youk et al., Reductions in arterial stiffness with weight loss in overweight and obese young adults: potential mechanisms, Atherosclerosis, vol. 223, no. 2, pp.485 490,2012. [46] C. P. Wang, W. C. Hung, T. H. Yu et al., Brachial-ankle pulse wave velocity as an early indicator of left ventricular diastolic function among hypertensive subjects, Clinical and Experimental Hypertension,vol.31,no.1,pp.31 43,2009. [47] G. F. Mitchell, H. Parise, E. J. Benjamin et al., Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study, Hypertension, vol. 43, no. 6, pp. 1239 1245, 2004. [48] A. Benetos, B. Waeber, J. Izzo et al., Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications, American Hypertension,vol.15, no.12,pp.1101 1108,2002. [49]P.V.Vaitkevicius,J.L.Fleg,J.H.Engeletal., Effectsofage and aerobic capacity on arterial stiffness in healthy adults, Circulation,vol.88,no.4,pp.1456 1462,1993. [50] S. S. Franklin, Arterial stiffness and hypertension: a two-way street? Hypertension,vol.45,no.3,pp.349 351,2005. [51] M. O Rourke, Arterial stiffness, systolic blood pressure, and logical treatment of arterial hypertension, Hypertension,vol.15, no. 4, pp. 339 347, 1990. [52] P. S. Douglas, The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk, the American College of Cardiology, vol.42,no.7,pp.1206 1207, 2003. [53] W.C.Yu,S.Y.Chuang,Y.P.Lin,andC.H.Chen, Brachialankle vs carotid-femoral pulse wave velocity as a determinant of cardiovascular structure and function, Human Hypertension,vol.22,no.1,pp.24 31,2008. [54] I.Nakae,S.Matsuo,T.Matsumoto,K.Mitsunami,andM.Horie, Augmentation index and pulse wave velocity as indicators of cardiovascular stiffness, Angiology, vol. 59, no. 4, pp. 421 426, 2008. [55] I. Ikonomidis, J. Lekakis, C. Papadopoulos et al., Incremental value of pulse wave velocity in the determination of coronary microcirculatory dysfunction in never-treated patients with essential hypertension, AmericanJournalofHypertension,vol. 21,no.7,pp.806 813,2008. [56] T.Weber,J.Auer,M.F.O Rourke,C.Punzengruber,E.Kvas,and B. Eber, Prolonged mechanical systole and increased arterial wave reflections in diastolic dysfunction, Heart,vol.92,no.11, pp.1616 1622,2006. [57] S. Laurent and P. Boutouyrie, Recent advances in arterial stiffness and wave reflection in human hypertension, Hypertension, vol. 49, no. 6, pp. 1202 1206, 2007. [58] W. P. Abhayaratna, W. Srikusalanukul, and M. M. Budge, Aortic stiffness for the detection of preclinical left ventricular diastolic dysfunction: pulse wave velocity versus pulse pressure, Journal of Hypertension,vol.26,no.4,pp.758 764,2008. [59] Y. Matsui, K. Eguchi, M. F. O Rourke et al., Differential effects between a calcium channel blocker and a diuretic when used in combination with angiotensin II receptor blocker on central aortic pressure in hypertensive patients, Hypertension,vol.54, no. 4, pp. 716 723, 2009.

MEDIATORS of INFLAMMATION The Scientific World Journal Gastroenterology Research and Practice Diabetes Research International Endocrinology Immunology Research Disease Markers Submit your manuscripts at BioMed Research International PPAR Research Obesity Ophthalmology Evidence-Based Complementary and Alternative Medicine Stem Cells International Oncology Parkinson s Disease Computational and Mathematical Methods in Medicine AIDS Behavioural Neurology Research and Treatment Oxidative Medicine and Cellular Longevity